title: Role of endothelin A receptor in colon cancer metastasis: in vitro and in vivo evidence.
abstract: The endothelin (ET)-1/endothelin A receptor (ETAR) axis is reportedly involved in tumor cell invasion, survival, and metastasis. However, the role of ETAR in colon cancer metastasis and the underlying mechanisms have not been defined. In the present study, we assessed the role of ETAR in colon cancer metastasis in vitro and in vivo. Overexpression and knockdown of ETAR were respectively performed in SW480 and SW620 human colon cancer cells. Overexpression of ETAR in SW480 cells significantly increased cell survival against cisplatin, cell invasion, and matrix metalloproteinase (MMP)-2 expression, which was strengthened by exogenous ET-1 and abolished by selective ETAR antagonist BQ123 and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Knockdown of ETAR in SW620 cells markedly decreased cell survival against cisplatin, cell invasion, and MMP-2 expression, which was strengthened by BQ123 and LY294002, and partially rescued by exogenous ET-1. In a colon cancer liver metastasis mouse model, while ETAR overexpression promoted colon cancer liver metastases, ETAR knockdown markedly decreased liver metastases. In conclusion, our in vitro data demonstrate that ETAR mediates the promoting effects of ET-1 on colon cancer cell survival, invasion and MMP-2 expression by a PI3K-mediated mechanism. Our in vivo data indicate that ETAR markedly promotes colon cancer liver metastasis. This study provides direct evidence for a critical role of ETAR in colon cancer metastasis, which suggests that ETAR antagonism could benefit patients with metastatic colon cancer.
authors.affiliation: Department of Geriatric Surgery, Second Xiangya Hospital, Central South University, Changsha, China; Department of Colorectal Surgery, Tumor Hospital, Xiangya School of Medicinel, Central South University, Changsha, China.
authors.forename: Shaolin
authors.initials: S
authors.lastname: Nie
authors.forename: Jumei
authors.initials: J
authors.lastname: Zhou
authors.forename: Fei
authors.initials: F
authors.lastname: Bai
authors.forename: Bonian
authors.initials: B
authors.lastname: Jiang
authors.forename: Juying
authors.initials: J
authors.lastname: Chen
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D044022:Receptor, Endothelin A / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D020778:Matrix Metalloproteinase 2; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D044022:Receptor, Endothelin A
keywords: cell survival; colon cancer; endothelin A receptor; endothelin-1; metastasis; phosphatidylinositol 3-kinase (PI3K)